Abstract
A complex interplay between nutritional status and reproductive function exists in mammals, such that fertility is suppressed during times of low energy availability. This metabolic control of fertility requires that the network of cells controlling GnRH drive must be able to receive and appropriately respond to information about changes in peripheral energy status. A range of metabolically relevant hormonal signals produced by peripheral organs, such as leptin, insulin and ghrelin, supply such information to the GnRH neurons and their network of afferent inputs. However, based on hormone and/or hormone receptor knockout mouse models, the only hormone that appears to be absolutely critical for fertility is leptin. Although leptin signals throughout the body, its central actions via brain neurons (but not GnRH neurons themselves) have been shown to be critical for occurrence of puberty onset and fertility. So far, no one population of neurons has been shown to be absolutely critical for metabolic control of fertility. Interestingly however, mice with leptin receptor knockout targeted to neuronal populations that produce the neurotransmitter GABA exhibit delayed puberty and subfertility in both sexes, while deletion of leptin receptors from GABAergic AgRP neurons leads only to delayed female puberty. This suggests leptin signals via a heterogenous and redundant network of GABAergic neurons to critically regulate GnRH neurons. In contrast, critical insulin targets are less well defined: while whole brain insulin receptor deletion causes a mild reproductive phenotype, neuronal insulin receptor deletion is without effect. This may be because insulin and leptin exert overlapping effects on fertility, and leptin signaling provides sufficient compensation in the absence of insulin signaling. A further example of multiple redundant systems may exist at the intracellular signaling level for metabolic hormone receptors, since deletion of signaling inhibitors known be involved in diet‐induced leptin and insulin resistance only temporarily protects mice from high calorie diet‐induced infertility, with eventual loss of fertility occurring in response to other mediators of hormone resistance.